We propose to study prospectively the relationships between lifestyle factors and risk of amyotrophic lateral sclerosis (ALS) among participants in the Cancer Prospective Study II (CPS II) of the American Cancer Society. The original cohort comprised 1,184,622 men and women from all 50 United States, the District of Columbia, and Puerto Rico, aged 30 years and older, who completed a lifestyle and dietary questionnaire in 1982. The proposed investigation will include the 1,098,726 participants who were alive on January 1, 1989, as reliable information on causes of death is only available after this date. During ten years of follow-up, 621 participants in this cohort died of ALS. Specifically, we will examine prospectively the associations between risk of ALS and cigarette smoking, use of antioxidant vitamins, education, occupation, and exposures to agricultural chemicals and solvents. Because of the large number of participants and long follow-up time this cohort provides a unique opportunity to examine prospectively the association between lifestyle variables and the risk of ALS among men and women. A further strength of the proposed investigation is the availability of information on several potential confounders, including past medical history, physical activity, and diet. Identification of the risk factors for ALS will provide clues about the etiology of the disease and contribute to identify those hypotheses that need more intense scrutiny in clinical or laboratory investigations.